Benzodiazepines are one of the most widely used class of drugs in therapy due to their anxiolytic and anticonvulsant properties. It is now well established that besides their interaction with specific recognition sites located in the brain, benzodiazepines bind to membranes prepared from various tissues containing the so-called peripheral-type benzodiazepine receptor site(s) (PBR). Benzodiazepines have been demonstrated to elicit their primary therapeutic actions in the central nervous system through specific binding sites on GABA-gated chloride channels. PBR are also abundant in neural tissue where they appear to be preferentially associated with astroglial cells.
The central nervous system is also known to synthesize steroids. Steroids have been demonstrated to be potent modulators of GABA.sub.A receptors, implying a physiological role of steroids as regulators of GABAergic transmission.
Heretofore, a certain known compound Ro 5-4864 of the benzodiazepine class was believed to stimulate PBR and as a result androgen production. See Ritta et al, Life Sciences; Vol. 40, pp. 791-798 (1987).
One problem with the benzodiazepine class of compounds in stimulating androgen production is that they, at therapeutic doses, do not selectively stimulate the peripheral-type benzodiazepine receptor, but rather, and as is well known, their primary pharmacological indication is for use as centrally acting anxiolytic or anticonvulsant agents. Another problem associated with the benzodiazepines is that therapeutic doses for stimulating steroidogenesis also stimulate the benzodiazepine receptors in the central nervous system.
Likewise, other agents such as the imidazopyridines have been known to have an affinity for the PBR. Langer et al, Pharmacol. Biochem. and Behavior (1988) Vol. 29 pp. 763-766 discuss the affinity of two imidazopyridines, i.e. zolpidem and alpidem for PBR. This paper is silent as to the use of these compounds for selectively stimulating steroidogenesis or the doses necessary to bring about this stimulation while at the same time minimally stimulating the centrally acting benzodiazepine receptors.
As a result, the present inventors have investigated which compounds would have a high affinity for PBR for stimulating steroidogenesis and yet have a low affinity for the centrally acting benzodiazepine receptors which are responsible for their anxiolytic and anticonvulsant properties.